Recent animal research suggests that corticosteroid down-regulation of the nicotine receptor, resulting in decreased sensitivity to nicotine's effects, may help to explain the phenomena of acute and chronic tolerance to nicotine. An implication of this observation for understanding nicotine self-administration via smoking in humans is that increased nicotine intake in the context of psychological stress or other conditions where corticosteroid levels are enhanced may represent behavioral compensation for situation-specific decreases in nicotine sensitivity. The long-term objective of the proposed project is to explore the role of corticosteroid mechanisms in modulating nicotine sensitivity and modifying nicotine self- administration in smokers. Over a 5-year period, three Phases of research will be conducted using repeated-measures designs with male subjects 21 to 45 years of age. The specific aims of Phase I are to determine the effects of corticosteroid activity upon nicotine self-administration via smoking by administering different doses of a synthetic corticosteroid, dexamethasone (IA); to test the possibility that increased nicotine intake following dexamethasone is the result of non-specific enhancement of smoking behavior by comparing the smoking of nicotine and non-nicotine cigarettes (IB); and to characterize the effects of different corticosteroid receptor agonists (fludrocortisone, hydrocortisone, and dexamethasone) upon sensitivity to nicotine, as defined by heart rate and cortisol increases and core temperature decreases in response to intravenous administration of a fixed dose of nicotine (IC). The objectives of Phase II are to examine the effects of different levels of a psychological stressor known to increase corticosteroid activity (mental arithmetic) on nicotine intake via smoking (IIA) and on sensitivity to nicotine following intravenous administration of a fixed nicotine dose(IIC); and to test the possibility that increased nicotine intake occurs as a side effect of stress-induced enhancement of smoking behavior by comparing the smoking of nicotine and non-nicotine cigarettes (IIB). The goal of Phase III is to study the interactions between nicotine dependence--reflecting differences in chronic tolerance-- and the variables studied in Phases I & II by varying the dosage od dexamethasone in both highly-dependent and less-dependent smokers (IIIA); to characterize the response to stress in such smokers by presenting different levels of a psychological stressor (IIIB); and to determine whether sensitivity to nicotine is associated irreversibly with history of nicotine use by examining the effects of nicotine infusion in highly- dependent smokers, less-dependent smokers, ex-smokers, and never-smokers following dexamethasone or placebo administration (IIIC). Overall, the project seeks to identify mechanisms whose elucidation may increase the understanding of smoking and nicotine dependence and lead to the development of new tools for treating smoking.